Project Summary In 2016 more than 1.9 billion adults were overweight and, of these, over 650 million were obese. Rising obesity rates have significant health consequences, contributing to increased rates of metabolic diseases including type 2 diabetes, steatosis, hypertension, and heart disease. Associations between obesity, insulin resistance and diabetes are complex, and how an increase in adiposity leads to metabolic and cardiovascular complications remains a critical gap in knowledge. Our exciting preliminary data show that the novel plasminogen receptor, Plg-RKT, is highly expressed in adipose tissue of lean mice and in response to a high fat diet (HFD), adipose expression of Plg-RKT is dramatically reduced. Furthermore, HFD-fed Plg-RKT-/- mice gain more weight, are more insulin resistant/glucose intolerant, and develop more hepatic steatosis than Plg-RKT+/+ littermates. These metabolic abnormalities are associated with increased adipose tissue macrophage accumulation and inflammation, increased adipose fibrosis and decreased expression of markers of adipogenesis. Furthermore, Plg-RKT expression is low in preadipocytes but dramatically increases during adipogenesis; an expression pattern consistent with pathways that promote adipogenesis. Thus, surprisingly, in addition to maintaining the anti-fibrotic, anti-inflammatory adipose environment, Plg-RKT coordinately regulates multiple aspects of adipose function that are also important to maintain efficient adipocyte function and metabolic homeostasis by directly promoting adipocyte adipogenesis and directly promoting adipocyte insulin sensitivity. Our long term goal to understand mechanisms by which Plg-RKT regulates physiologic and pathologic processes.! Our objective in this application is to determine mechanisms by which Plg-RKT regulates adipose function and systemic metabolism, as unifying mechanisms that maintain healthy adipocytes as well as limit chronic adipose inflammation and ectopic lipid deposition. The central hypothesis to be addressed is that Plg-RKT promotes healthy adipocyte function and maintains systemic metabolic homeostasis by coordinately regulating adipogenesis, insulin signaling, inflammation and fibrosis. To test our hypothesis our specific aims are: 1) To elucidate the role of Plg-RKT in adipogenesis; 2) To determine the role of Plg-RKT in regulation of insulin sensitivity; 3) To determine mechanisms by which Plg-RKT inhibits fibrosis and inflammation in obesity; and 4) To perform preclinical studies to test the effects of over-expression of Plg-RKT in vivo. We will employ a diet induced obesity model in mice with global and tissue specific (adipose and macrophage) deletion of Plg-RKT, mice with global and tissue specific overexpression of Plg-RKT, and mice doubly deficient for Plg-RKT and fibrinogen. Innovation lies in the investigation of a novel plasminogen receptor as a crucial focal point for regulation of multiple key aspects of adipose function. The studies proposed are significant because new knowledge of mechanisms by which adipose function and systemic metabolic homeostasis are maintained will be acquired, with translational potential for drug development.